| Summary: | Abstract Osteosarcoma (OS) is the primary malignant bone tumor. Despite therapeutic strategies including surgery, chemotherapy, and radiotherapy have been introduced into the war of fighting OS, the 5‐year survival rate for patients still remains unchangeable for decades. Besides, the critical bone defects after surgery, drug‐resistance and side effects also attenuate the therapeutic effects and predict poor prognosis. Recently, photothermal therapy (PTT) has attracted extensive attention featuring minimal invasiveness and high spatial‐temporal precision characteristics. Herein, an ultrathin 2D inorganic ancient pigment Egyptian blue decorated 3D‐printing scaffold (CaPCu) with profound PTT efficacy at the second near‐infrared (NIR‐II) biowindow against OS and enhanced osteogenesis performance is successfully constructed. Importantly, this work uncovers the underlying biological mechanisms that genes associated with cell death, proliferation, and bone development are regulated by CaPCu‐scaffold‐based therapy. This work not only elucidates the fascinating clinical translation prospects of CaPCu‐scaffold‐based PTT against OS in NIR‐II biowindow, but also demonstrates the potential mechanisms and offers a novel strategy to develop the next‐generation, multifunctional tissue‐engineering biomaterials.
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